Glucagon-Like Peptide-1 Receptor Agonist Treatment in Adult, Obesity-Related, Symptomatic Asthma

项目摘要 肥胖显然对哮喘是有害的，但我们缺乏治疗独特的肥胖哮喘表型的工具。 同时肥胖影响40%的成人哮喘，并增加哮喘的严重程度、症状和 同时降低传统疗法的疗效。2-5我们的长期目标是 开发针对肥胖哮喘表型的呼吸道炎症的新疗法。我们的总体目标， 是我们临床前和初步临床研究结果的下一步，是确定 高血糖素样多肽-1受体激动剂(GLP-1RA)对哮喘控制、呼吸道和脂肪炎症的作用 在患有肥胖性哮喘的成年人中。我们的中心假设是GLP-1RA改善哮喘控制和减少 肥胖性哮喘对呼吸道的直接影响引起的呼吸道炎症。以生成证明- 支持GLP-1RA在肥胖性哮喘表型和试验中的确定性3期临床试验的概念数据 我们的中心假设，我们提出了以下具体目的：1)确定GLP-1RA的疗效 哮喘控制和评估肥胖哮喘的耐受性，以及2)确定GLP的组织特异性影响- 1RA对肥胖性哮喘患者呼吸道炎症和脂肪的影响。在为期12周的双盲、随机、 每日一次口服赛马路德7 mg的安慰剂对照试验，用于肥胖相关的有症状的成人受试者 在没有DMII的情况下，我们将测试赛马路德改善哮喘控制的假设(目标1a)，是 可耐受(目标1b)，并减少2型和非2型气道炎症，与体重减轻无关(目标2)。 主要的临床结果将从ACQ-7的基线改变。主要的机械性结果将是 血清Periostin水平较基线有变化。因为胰岛素抵抗在肥胖和基线血液中是可变的 嗜酸性粒细胞计数通常可以预测哮喘治疗的反应，这些标记物将用于 预先指定的子组分析。基线时的腹部皮下脂肪和呼吸道样本 治疗5周和12周将使用RNA测序进行比较，以检验GLP-1RA的假设 减少炎症以恢复呼吸道的动态平衡与脂肪组织的变化相反 肥胖哮喘。这一建议有助于收集必要的临床、机械性和耐受性 为GLP-1RA治疗哮喘的最终III期临床试验的设计提供信息的数据。因此，它支持 一种新的哮喘治疗类别的快速发展，并代表着方法的范式转变 靶向调节上游代谢通路的哮喘治疗干预 跨越多个器官系统的炎症，可能是疾病的改善，最终是糖皮质激素的节省。

Project Summary Obesity is clearly detrimental in asthma, yet we lack tools to treat the unique obese asthma phenotype. Comorbid obesity impacts >40% of adult asthmatics1 and increases asthma severity, symptoms and exacerbations while simultaneously reducing the efficacy of conventional therapies.2-5 Our long-term goal is to develop novel treatments for airway inflammation in the obese asthma phenotype. Our overall objective, which is the next step in translating our preclinical and preliminary clinical findings, is to determine the impact of glucagon-like peptide-1 receptor agonists (GLP-1RA) on asthma control and airway and adipose inflammation in adults with obese asthma. Our central hypothesis is that GLP-1RA improve asthma control and reduce airway inflammation due to direct effects on the respiratory tract in obese asthma. To generate the proof-of- concept data to support definitive phase 3 clinical trials of GLP-1RA in the obese asthma phenotype and test our central hypothesis, we propose the following specific aims: 1) Determine the efficacy of GLP-1RA on asthma control and assess tolerability in obese asthma and 2) Determine the tissue-specific impact of GLP- 1RA on inflammation in the airway and adipose in obese asthma. In a 12-week double-blind, randomized, placebo-controlled trial of oral semaglutide 7 mg once daily in adult subjects with obesity-related, symptomatic asthma without DMII, we will test the hypotheses that semaglutide improves asthma control (aim 1a), is tolerated (aim 1b) and reduces type-2 and non-type 2 airway inflammation independent of weight loss (aim 2). The primary clinical outcome will be change from baseline in ACQ-7. The primary mechanistic outcome will be change from baseline in serum periostin. Because insulin resistance is variable in obesity and baseline blood eosinophil counts are often predictive of response to asthma therapeutics, these markers will be used for prespecified subgroup analyses. Subcutaneous abdominal adipose and respiratory tract samples at baseline and 5 and 12 weeks of therapy will be compared using RNA sequencing to test the hypothesis that GLP-1RA reduce inflammation to restore homeostasis in the respiratory tract opposite to changes in adipose tissue in obese asthma. This proposal facilitates the collection of the necessary clinical, mechanistic, and tolerability data to inform the design of a definitive phase III clinical trial of a GLP-1RA in asthma. It thereby supports the rapid development of a novel therapeutic class for asthma and represents a paradigm shift in the approach to therapeutic intervention in asthma through the targeting of a metabolic pathway which regulates upstream inflammation across multiple organ systems, may be disease modifying, and ultimately glucocorticoid sparing.